It is the goal of our Program Project to investigate the pathogenesis of neurofirbrillary tangles and neuritic and amyloid plaques in Alzheimer's disease. To do this we have developed an integrated program aimed at defining the constituent polypeptides of the amyloid fibers and paired helical filaments (PHF) by isolating and determining the amino acid sequence of the constituent polypeptides. This information will be used to prepare amyloid and PHF specific antibodies, cDNA probes, and synthetic amyloid and PHF peptides. These reagents will be used to (1) identify the cells responsible for abnormal fiber formation, (2) investigate the synthesis of amyloid and PHF polypeptides and their assembly in fibers, (3) identify amyloid and PHF specific epitopes and establish their structural relationship to amyloid fiber and PHF, and (4) identify and evaluate candidate precursor proteins in both the normal and AD/SDAT CNS, serum and CSF.